20-17969694-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_052865.4(MGME1):c.-59-107T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 677,250 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (32 hom., cov: 33)
  • Exomes 𝑓: 0.019 (124 hom.)
• Consequence: MGME1 NM_052865.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.120

Genes affected

MGME1 (HGNC:16205): (mitochondrial genome maintenance exonuclease 1) The protein encoded by this gene is a nuclear-encoded mitochondrial protein necessary for the maintenance of mitochondrial genome synthesis. The encoded protein is a RecB-type exonuclease and primarily cleaves single-stranded DNA. Defects in this gene have been associated with mitochondrial DNA depletion syndrome-11. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2015]

OVOL2 (HGNC:15804): (ovo like zinc finger 2) This gene encodes a member of the evolutionarily conserved ovo-like protein family. Mammalian members of this family contain a single zinc finger domain composed of a tetrad of C2H2 zinc fingers with variable N- and C-terminal extensions that contain intrinsically disordered domains. Members of this family are involved in epithelial development and differentiation. Knockout of this gene in mouse results in early embryonic lethality with phenotypes that include neurectoderm expansion, impaired vascularization, and heart anomalies. In humans, allelic variants of this gene have been associated with posterior polymorphous corneal dystrophy. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 20-17969694-T-G is Benign according to our data. Variant chr20-17969694-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 1196344.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0161 (2456/152298) while in subpopulation AMR AF= 0.0285 (435/15286). AF 95% confidence interval is 0.0263. There are 32 homozygotes in gnomad4. There are 1180 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MGME1	NM_052865.4	c.-59-107T>G		intron_variant		ENST00000377710.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MGME1	ENST00000377710.10	c.-59-107T>G		intron_variant		1	NM_052865.4	P1
MGME1	ENST00000377704.4	c.-59-107T>G		intron_variant		3
MGME1	ENST00000377709.1	c.-59-107T>G		intron_variant		2
OVOL2	ENST00000486776.5	n.492-12657A>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2456 AN: 152180 Hom.: 32 Cov.: 33

Gnomad AFR AF: 0.00393

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0285

Gnomad ASJ AF: 0.0204

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00684

Gnomad FIN AF: 0.0104

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0229

Gnomad OTH AF: 0.0220

GnomAD4 exome AF: 0.0193 AC: 10121 AN: 524952 Hom.: 124 AF XY: 0.0192 AC XY: 5184 AN XY: 270684

Gnomad4 AFR exome AF: 0.00316

Gnomad4 AMR exome AF: 0.0192

Gnomad4 ASJ exome AF: 0.0222

Gnomad4 EAS exome AF: 0.0000674

Gnomad4 SAS exome AF: 0.0115

Gnomad4 FIN exome AF: 0.0106

Gnomad4 NFE exome AF: 0.0230

Gnomad4 OTH exome AF: 0.0182

GnomAD4 genome AF: 0.0161 AC: 2456 AN: 152298 Hom.: 32 Cov.: 33 AF XY: 0.0158 AC XY: 1180 AN XY: 74468

Gnomad4 AFR AF: 0.00392

Gnomad4 AMR AF: 0.0285

Gnomad4 ASJ AF: 0.0204

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00684

Gnomad4 FIN AF: 0.0104

Gnomad4 NFE AF: 0.0229

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0172 Hom.: 5

Bravo AF: 0.0168

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 07, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	5.9
Dann	Benign	0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs142001430; hg19: chr20-17950337;